4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase

Abstract

Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.

The invention claimed is: 
     
       1. A method of treating a disease mediated by 12-lipoxygenase, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, F, Cl, Br, amine, nitrogen dioxide, indole, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, wherein said aryl, heterocycloalkyl, heteroaryl, are optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, F, Cl, Br, hydroxyl, amine, and methoxy, wherein R 1  and R 2  are not both H; 
         R 3  is selected from the group consisting of phenyl, cycloalkyl, heterocycloalkyl, aryl, benzothiazole, benzoxazole, imidazole, benzimidazole, thiophene, 1-naphthalene, 2-naphthalene, quinoline, isoquinoline, 4N-boc-piperidine-3-phenyl, oxazole, benzothiophene, parathiazine, furan, pyran, chromene, benzofuran, pyrrole, pyrazole, triazine, indole, purine, and phthalazine; wherein said phenyl, cycloalkyl, heterocycloalkyl, aryl, benzothiazole, benzoxazole, imidazole, benzimidazole, thiophene, 1-naphthalene, 2-naphthalene, quinoline, isoquinoline, 4N-boc-piperidine-3-phenyl, oxazole, benzothiophene, parathiazine, furan, pyran, chromene, benzofuran, pyrrole, pyrazole, triazine, indole, purine, and phthalazine are optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, F, Cl, Br, hydroxyl, amine, alkoxy, phenyl, cycloalkyl, aryl, piperazine, piperidine, pyridine, morpholine, pyrrolidine, pyrazolidine, imidazolidine, and thiomorpholine; 
         or a pharmaceutically acceptable salt thereof, 
         wherein the disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, diabetic kidney disease, diabetic neuropathy disease, cardiovascular disease, heparin induced thrombocytopenia, thrombosis, anti-phospholipid syndrome; thrombosis associated with therapeutic or diagnostic monoclonal antibodies; and cancer, wherein the cancer is selected from the group consisting of prostate cancer, colorectal cancer, breast cancer, and lung cancer. 
       
     
     
       2. The method of  claim 1 , wherein R 1  is selected from the group consisting of methoxy and Cl when R 2  is H;
 R 2  is selected from the group consisting of Br, and Cl when R 1  is H; and 
 R 3  is selected from the group consisting of 2-benzothiazole, 2-benzoxazole, 2-benzimidazole, 4-methyl-2-benzothiazole, 2-thiophene, phenyl, 1-naphthalene, 2-naphthalene, 1,4-bi-phenyl, 1,3-biphenyl, 3-piperazine-phenyl, 4-piperidine-phenyl, 4-piperazine-3-pyridine, 3-quinoline, 8-isoquinoline, 2-pyridine, 3-pyridine, 3-tertbutyl-phenyl, 3-methoxy-phenyl, 6-methoxy-2-benzothiazole, 6-fluro-2-benzothiazole, 3-morpholine-phenyl, 4N-boc-piperidine-3-phenyl, 3-piperidine-phenyl, and 3-isopropyl-phenyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       3. The method of  claim 1 , wherein R 1  is methoxy and R 2  is H. 
     
     
       4. The method of  claim 1 , wherein R 3  is phenyl, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, F, Cl, Br, hydroxyl, amine, alkoxy, phenyl, cycloalkyl, aryl, piperazine, piperidine, pyridine, morpholine, pyrrolidine, pyrazolidine, imidazolidine, and thiomorpholine. 
     
     
       5. The method of  claim 2 , wherein R 1  is methoxy and R 2  is H. 
     
     
       6. The method of  claim 5 , wherein R 3  is phenyl substituted with one or more substituents selected from the group consisting of F, Cl and Br. 
     
     
       7. The method of  claim 6 , wherein R 3  is phenyl substituted with F. 
     
     
       8. The method of  claim 1 , wherein the compound is a compound of formula (II) 
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of O, S, NH, and C; 
         wherein R 1  and R 2  are independently selected from the group consisting of H, halogen, hydroxyl, alkoxy, and alkyl; 
         wherein R 3  through R 6  are independently selected from the group consisting of H, halogen, alkoxy, and alkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       9. A method of treating a disease mediated by 12-lipoxygenase, comprising administering to a patient in need thereof an effective amount of a compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein R1 and R2 are independently selected from the group consisting of H, halogen, and alkoxy, and further wherein R1 and R2 are not both H; 
         wherein R4 and R5 are independently selected from the group consisting of H, alkyl, phenyl, and optionally substituted phenyl; 
         or a pharmaceutically acceptable salt thereof; with the proviso that the compound is not 
       
       
         
           
           
               
               
           
         
         and wherein the disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, diabetic kidney disease, diabetic neuropathy disease, cardiovascular disease, heparin induced thrombocytopenia, thrombosis, anti-phospholipid syndrome; thrombosis associated with therapeutic or diagnostic monoclonal antibodies; and cancer, wherein the cancer is selected from the group consisting of prostate cancer, colorectal cancer, breast cancer, and lung cancer. 
       
     
     
       10. The method of  claim 1 , wherein the compound is a compound of formula (IV) 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from the group consisting of H, halogen, and alkoxy; 
         wherein R 3  and R 4  are independently selected from the group consisting of H, phenyl, optionally substituted phenyl, tert-butyl, isopropyl, and 
       
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of NH, O, and 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       11. The method of  claim 1 , wherein the disease is Type 1 diabetes or Type 2 diabetes. 
     
     
       12. The method of  claim 1 , wherein the disease is diabetic kidney disease or diabetic neuropathy. 
     
     
       13. The method of  claim 1 , wherein the disease is cardiovascular disease, wherein the cardiovascular disease is selected from the group consisting of congestive heart failure, myocardial infarction and stroke. 
     
     
       14. The method of  claim 1 , wherein the disease is selected from the group consisting of thrombosis, heparin-induced thrombocytopenia; anti-phospholipid syndrome; and thrombosis associated with therapeutic or diagnostic monoclonal antibodies. 
     
     
       15. The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and the disease is Type 1 or Type 2 diabetes. 
       
     
     
       16. The method of  claim 1  wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and the disease is Type 1 or Type 2 diabetes. 
       
     
     
       17. The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and the disease is selected from the group consisting of Type 1 diabetes, Type 2 diabetes, diabetic kidney disease and diabetic neuropathy disease. 
       
     
     
       18. The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       19. The method of  claim 14 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       20. The method of  claim 19  wherein the disease is disease is selected from the group consisting of heparin induced thrombocytopenia, thrombosis, anti-phospholipid syndrome; and thrombosis associated with therapeutic or diagnostic monoclonal antibodies.